Type 2 diabetes mellitus is a metabolic disorder characterized by hyperglycemia (high blood sugar) resulting from insulin deficiency (the inability of the body to produce sufficient insulin) or insulin resistance (the inability of the body to use insulin properly). Chronic hyperglycemia is likely to worsen type 2 diabetes mellitus, as excessive glucose in the blood can damage the pancreas (and thus impair insulin release, a condition which can become permanent) and contribute to insulin deficiency. Long-term complications of type 2 diabetes mellitus include heart disease, stroke, diabetic retinopathy, kidney failure, and poor blood circulation to the limbs, which may require amputation.
Long term hyperglycemia is monitored by periodic measurement of a subject's hemoglobin A1c (HbA1c) levels. HbA1c levels reflect a subject's average blood glucose levels over the previous two to three months. Studies have shown that the incidences of clinical complications from type 2 diabetes are significantly associated with a subject's degree of hyperglycemia, as indicated by HbA1c levels. In the UK Prospective Diabetes Study (UKPDS), incidence rates for any end point related to diabetes (e.g., fatal or non-fatal myocardial infarction, amputation or death from peripheral vascular disease, and fatal or non-fatal microvascular disease) was three-fold greater for subjects in the highest HbA1c level category, e.g., greater than or equal to 10%, when compared to subjects with HbA1c of less than 6%. Furthermore, the UKPDS study showed that there are many benefits from reducing a high HbA1c level; as examples, reducing HbA1c levels by 1% results in a 14% decrease in risk of fatal or non-fatal myocardial infarction, a 12% decrease in risk of fatal or non-fatal stroke, a 21% decrease in risk of diabetes-related death, a 43% decrease in risk of amputation, and a 37% decrease in risk of small blood vessel disease (e.g., retinal blood vessel disease causing vision loss). Methods for reducing HbA1c levels in subjects with type 2 diabetes, particularly those with high (e.g., >10%) HbA1c levels, is warranted.
A variety of drug dosage forms and methods of drug administration have been developed for delivery of drugs to mammals, in particular, for delivery of drugs to humans (see, e.g., the Merck Manual of Diagnosis and Therapy, 18th edition, Published by Merck Sharp & Dohme Corp., Whitehouse Station, N.J.). Such dosage forms include, for example, use of the following routes of administration: oral; injection (e.g., intravenously, intramuscularly, intrathecally, subdermally, and subcutaneously); implantation (e.g., subcutaneous); and across a skin or mucosal barrier (e.g., sublingual, rectal, vaginal, ocular, nasal, inhalation into the lungs, topical, and transdermal). Each route of administration has specific purposes, advantages, and disadvantages.
The oral route of administration is the most common and generally considered to be the most convenient. Oral administration, however, poses some limitations because drugs administered by this route can be subject to inter- and/or intra-subject variability and result in variable 24 hour plasma drug exposure. Other routes of administration may be required when the oral route cannot be used.
When drugs are prepared for administration by injection (e.g., subcutaneous, intramuscular, intravenous, and intrathecal administration), the drug can be formulated in a variety of ways including formulations that prolong drug absorption from the injection site for hours, days, or longer. Such formulations are typically used for subcutaneous injection. Injectable products formulated for prolonged delivery typically are not administered as often as injectable drug products having more rapid absorption. Subcutaneous administration is used for many protein or peptide drugs because such drugs are typically broken down by the digestive system to inactive forms if taken orally. Subcutaneous administration of a drug typically requires frequent self-injection, for example, one or more times daily or once-weekly injections.
When a large volume of a drug product is required, intramuscular administration is generally the preferred route of administration. Typically, intramuscular administration of drugs is by injection into the muscle of the upper arm, thigh, or buttock. The rate of drug absorption into the bloodstream in large part depends on the blood supply to the muscle, that is, the more blood supply the faster the drug is absorbed.
Intravenous drug administration requires that a needle be inserted directly into a vein. A drug may be given in a single dose or continuously infused. For infusion, a drug solution is either delivered using gravity (e.g., from a collapsible plastic bag) or using an infusion pump through a tube inserted in a vein, usually in the forearm. An intravenous injection can be more difficult to administer than a subcutaneous or intramuscular injection, for example, because inserting a needle or catheter into a vein may be difficult, drugs typically must be mixed within a relatively short time before beginning administration, there is an increased chance of infection (e.g., abscessed infections of injection sites caused by lack of hygiene and/or a lack of correct aseptic technique), and over time there is scarring damage to the peripheral veins.
When drugs are administered by intravenous injection it is often desirable for health care practitioners to closely monitor subjects for signs that the drug is working and that the drug is not causing undesired side effects. Typically, the effect of intravenously administered drugs tends to last for a shorter periods of time than drugs administered by subcutaneous injection or intramuscular injection. Therefore, some drugs must be administered by continuous infusion to provide appropriate therapeutic effect. Because of the difficulties associated with intravenous drug administration it is most typically used in hospital or skilled care settings; it is rarely used for long-term self-administered treatment.
A number of complications negatively impact compliance with injection treatment regimens, including, but not limited to, the following. For a subject that is needle phobic, this is particularly troublesome when a drug must be self-injected over extended periods of time. Compliance can also be complicated by the inconvenience of administration of a drug by injection, for example, when subjects are in public or busy with daily activities. Also, frequent self-administration of a drug reminds subjects of their disease state and carries a stigma associated with the disease and/or treatment. Additionally, there is a risk of depot of drug at injection site, such as when the drug does not sufficiently or rapidly diffuse or distributed into adjoining tissues. Such depot can lead to undesirable immune reactions, e.g., immune complex formation, inflammation, and high antibody titer, and/or can lead to local swelling, redness, and pain.
The implantable osmotic delivery devices of the present invention, and use of these osmotic delivery devices in methods for the treatment of diseases or conditions in subjects in need of treatment, uniquely address unmet needs of previously described drug dosage forms and methods of treatment. For example, the present invention provides treatment of subjects at a target drug dose that is continuously administered over time with the ability to rapidly establish and sustain over time substantial steady-state drug delivery while also providing the ability to rapidly terminate administration of the drug. Heretofore, drug administration via injection has not typically been able to provide rapid establishment and long-term maintenance (e.g., three months or more) of steady-state drug delivery and, even if that were possible, treatment using drugs administered by injection (e.g., drugs formulated for prolonged delivery) has not been able to be rapidly terminated. The present invention also provides for enhanced tolerization of subjects to drug dose escalation relative to dose escalation performed by administration of drug by injection.
The clinical challenges encountered with long-term pharmacological treatment of type 2 diabetes include hypoglycemia, weight gain, and side effects and aversion to self-injection, which often contribute to poor adherence and persistence with therapy. Poor adherence and persistence with antidiabetic therapy are common; a systematic review of the literature reported that adherence rates to oral drugs ranged from 36% to 93% and for insulin was approximately 60%, and a recent report found discontinuation rates >80% with Glucagon-like peptide-1 receptor agonists (GLP-1 RAs; a class of drug for treating type 2 diabetes) at 12 months. An evaluation of persistence with injectable antidiabetic agents, including insulin and an exenatide, found that only 28.7% of patients persisted with therapy to 1 year. Much of this non-adherence may be because of the inconvenience and discomfort associated with injectable antidiabetic drugs. The consequences of poor adherence include inadequate glycemic control, increased morbidity and mortality, impacts on the benefit/risk ratio of a drug and overall tolerability, and markedly increased healthcare costs. Many interventions have been studied and recommended to increase medication adherence, but most require extensive and continuous use of costly healthcare resources, and the beneficial effects on adherence are temporary. These concerns about poor compliance and adherence are abrogated by the use of an osmotic delivery device and formulations useful in the present invention.